Japanese Journal of Clinical Oncology 31:553-556 (2001)
© 2001 Foundation for Promotion of Cancer Research
A Case with HER2-overexpressing Breast Cancer Completely Responded to Humanized anti-HER2 Monoclonal Antibody
1Department of Surgery, Tokai University School of Medicine, Isehara, Kanagawa, 2National Cancer Center Hospital, Tokyo, 3National Cancer Center Hospital East, Kashiwa, Chiba and 4Mitsubishi-Tokyo Pharmaceuticals, Inc., Research Center, Kisarazu, Chiba, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentREFERENCES |
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This is a case report of a 57-year-old woman with a history of primary carcinoma of the right breast with metastases to the contralateral axillary lymph node. After a partial response (PR) was induced by high-dose chemotherapy with peripheral blood stem cell transplantation, she underwent mastectomy with biopsy of the bilateral axillary lymph nodes. Six months after surgery, the patient had multiple lung metastases. She was then treated with five cycles of fluorouracil, mitoxantrone and vindesine. Although a PR was achieved, further chemotherapy could not be given because of cardiac dysfunction. Since immunohistochemical staining for the HER2 gene product was strongly positive on the surface of primary tumor cells, humanized anti-HER2 monoclonal antibody (trastuzumab) was given intravenously. The metastatic lesion decreased in size and finally appeared to be only cicatricial. Twenty-one months after the initial administration of trastuzumab, the pulmonary lesion was excised. The pathological examination revealed no tumor cells in the resected specimen so further treatment was stopped. The relapse-free state has continued for 24 months after the pulmonary resection.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentREFERENCES |
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Proto-oncogenes encode growth factors and their receptors. These genes participate in the development of human malignancies (1). The c-erbB-2/HER2 proto-oncogene encodes a 185 kDa transmembrane glycoprotein receptor (p185HER2) that has partial homology with the epidermal growth factor receptor (2–6). The HER2 product is made up of extracellular, transmembrane and intracellular domains. The intracellular domain has tyrosine kinase activity. Various adenocarcinomas including breast cancer have considerable amplification with occasional overexpression of this gene (7,8). At the lowest estimate, one quarter of human breast cancers overexpress the HER2 gene (8,9). The HER2 overexpression in breast cancer patients is associated with a poor prognosis independent of axillary nodal status (8,10,11). Experimental results suggest that the HER2 gene increases the clinical severity of tumors by the overexpression of HER2 (12–14). However, this gene is also expressed, but faintly, in normal tissues (15,16). Therefore, p185HER2 is considered to be a favorable target for immunological therapy. Monoclonal antibodies directed against p185HER2 have been synthesized (17).
Several studies have reported that murine monoclonal antibodies (mAbs) against p185HER2 possess anti-tumor effects (17–25). However, the clinical application of murine mAbs would be restricted by a human anti-mouse antibody (HAMA) response (26,27).
A humanized anti-HER2 monoclonal antibody (trastuzumab) was produced from the antigen-binding loops of the murine monoclonal antibody 4D5 against the HER2 gene product by adding human variable region residues to IgG1 constant domains (28). Clinical studies of trastuzumab showed some objective responses without emergence of HAMA (29–32). A large prospective randomized trial compared chemotherapy plus trastuzumab with chemotherapy alone in treatment for HER2 overexpressing metastatic breast cancer (33). We report here a case of metastatic breast cancer refractory to chemotherapeutic agents, but which responded well to therapy with trastuzumab.
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CASE REPORT |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentREFERENCES |
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The patient was a 57-year-old, married, parous woman with a chief complaint of right breast mass at the time she was admitted to the Tokai University Hospital on April 5, 1995. Primary right breast cancer with the contralateral axillary metastasis (T2N1bM1, Stage IV) was confirmed. The results of a quantitative analysis of estrogen receptors (ER) and progesterone receptors (PgR) in the specimen were negative. On June 1, 1995, induction chemotherapy consisting of one course of cyclophosphamide 500 mg/m2, doxorubicin 40 mg/m2 and fluorouracil 500 mg/m2 was administered. After recognition of a partial response (PR), two courses of epirubicin 130 mg/m2 and cyclophosphamide 1000 mg/m2, at an interval of 3 weeks, were given and peripheral blood stem cells (PBSC) harvested. Subsequent to this induction chemotherapy, PBSC transplantation plus high-dose chemotherapy (HDC) with thiotepa 200 mg/m2/d and cyclophosphamide 2000 mg/m2/d was administered for 3 days. On September 6, 1995, a right mastectomy with sampling of the bilateral axillary nodes was performed. Pathological examinations of the resected specimen revealed cicatricial tissues with some residual cancer cells both in the breast and in the lymph nodes.
On October 21, 1996, multiple lung metastases were detected ~15 months after the administration of HDC with PBSCT (Fig. 1a). The patient was given five courses of treatment consisting of mitoxantrone 6 mg/m2 and vindesine 2.4 mg/m2 on day 1 and fluorouracil 500 mg/m2 on days 1–5, as a salvage regimen. The treatment was administered every 3 weeks until cardiac dysfunction with reduced ejection fraction, possibly due to the mitoxantrone, was manifested. This was considered a PR (Fig. 1b).
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Immunohistochemical staining for the HER2 gene product was strongly positive on the surface of primary tumor cells, as shown in Fig. 2. The patient then received recombinant humanized anti-HER2 mAb (trastuzumab), which recognized the extracellular domain of the HER2 product. Trastuzumab was produced as described by Carter et al. (28). The institutional review board of Tokai Hospital approved the clinical use of trastuzumab and the patient gave informed consent. Trastuzumab was administered intravenously, with a consistent infusion speed, for 90 min without any infusion reactions. The starting dose of trastuzumab on April 21, 1997 was 4 mg/kg, followed in 3 weeks by weekly doses. The metastatic lesions in the lung decreased in size and finally appeared to be only cicatricial without severe adverse events (Fig. 1c). On February 10, 1999, 21 months after the initial administration of humanized anti-HER2 monoclonal antibody, pulmonary tissue from segments 1, 2 and 6, which mimicked the cicatrices on the chest X-ray, were excised. The pathological examination revealed no tumor cells (Fig. 3). Immunohistochemical staining of these tissues was negative for the HER2 product. After the surgery, trastuzumab was not administered. The relapse-free state has continued for 24 months.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentREFERENCES |
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p185HER2 is considered to be a suitable target for immunological therapy of those tumors overexpressing HER2. Murine mAbs against the HER2 gene product have been produced and examined for anti-tumor potency. However, the clinical use of murine mAbs is restricted because of the human anti-mouse antibody reaction. In preclinical studies, it was suggested that a humanized antibody would have the same or greater anti-tumor potency than murine mAbs (34). Therefore, a humanized antibody against the HER2 gene product would have great potential.
A clinical trial to elucidate the efficacy of rhuMAb HER2 (trastuzumab) against HER2-overexpressing metastatic breast cancer demonstrated that trastuzumab induced durable objective responses (32). In the trial, 222 women were enrolled. The patients with HER2-overexpressing metastatic breast cancer had shown disease progression after one or two chemotherapy regimens. Of the analyzed cases, 55% were negative for ER and 59% were negative for PgR; 38% of cases were disease-free for 12 months or less, 72% had liver or lung metastases, 68% had had two or more prior chemotherapeutic regimens and 26% had had prior bone marrow or stem-cell transplantation. Trastuzumab was administered intravenously at a loading dose of 4 mg/kg, then given weekly at a maintenance dose of 2 mg/kg; 20% of the patients had chills or fever at the initial infusion, but only 
5% had the same symptoms after the second infusion. Frequent adverse events were pain (48%), asthenia (46%), fever (38%), chills (36%) and vomiting (28%). Cardiac events such as congestive heart failure, cardiomyopathy and a decrease in ejection fraction were observed in 10 (4.7%) of the 213 patients analyzed. One patient who had received a prior doxorubicin dose of 450 mg/m2 died after receiving the eighteenth infusion of trastuzumab. Eight complete responses (CRs) (2%) and 26 PRs (12%) in the 222 patients enrolled were achieved. The overall response rate by intent-to-treat analysis was 15% (95% CI, 11–21). The median duration of response was 9.1 months (2–26+) and the median survival time was 13 months. The QOL score was hardly affected by the therapy.
Our case had several unfavorable conditions for treatment. The patient had received high-dose chemotherapy and had also had cardiac dysfunction, possibly due to previous chemotherapy with mitoxantrone. The primary tumor was negative for both ER and PgR. Nevertheless, the patient had a pathological CR without serious adverse events. To date, the patient has been relapse-free for over 24 months.
At the Annual Meeting of the American Society of Clinical Oncology in 2000, the results of a randomized trial using trastuzumab as a first-line therapy against progressive metastatic breast cancer with no previous chemotherapy were presented (35). Of the 114 women enrolled, 68% had received adjuvant chemotherapy; 76% of the patients were immunohistochemically positive (3+) for HER2 protein. Seven CRs and 23 PRs were observed in the 114 patients. The overall response rate by intent-to-treat analysis was 26% (95% CI, 18–34). Thirteen of the patients had a stable disease lasting more than 6 months (SD). The total number of CRs, PRs and SD in the 114 patients was 43 (38%; CI, 29–47).
In the USA, the FDA approved trastuzumab in late 1998. In Japan, the clinical use of trastuzumab has just become available in 2001. The optimal use of trastuzumab in the treatment of HER2-overexpressing breast cancer should be elucidated by various clinical trials.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONCASE REPORTDISCUSSIONAcknowledgmentREFERENCES |
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This work was supported in part by Grants-in-Aid from the Ministry of Health and Welfare of Japan.
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FOOTNOTES |
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+ For reprints and all correspondence: Yutaka Tokuda, Department of Surgery, Tokai University School of Medicine, Bohseidai, Isehara, Kanagawa 259-1193, Japan. E-mail: tokuda@is.icc.u-tokai.ac.jp
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REFERENCES |
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Received June 14, 2001; accepted August 14, 2001.
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